Queenstown ACHD meeting 2017

Neurocognitive outcomes and interventions in ACHD survivors

William Wilson, MBBS FRACPRoyal Melbourne Hospital

Australia

EXPANDED FOCUS:Mortality patient centred outcomes

Overview

1. What do mean by neurocognitive outcomes?

2. Why do we anticipate higher rates of neurocognitive difficulties in ACHD patients and what data is there available?

3. (How) can we intervene?

What do we mean by neurocognitive outcomes?

IQ testing

Several standardised tests available

– Most common: WAIS (Wechsler Adult Intelligence Scale)

Scores are age adjusted and converted to an IQ score

– Normalised distribution

– Not linear, not a percentage Borderline 70-79 ‘Average’ 90-110

Subscales of IQ score

Additional testing components?

Memory

Academic achievement

Visual motor integration

Attention

Executive function

Executive function: Group of processes that control & regulate other cognitive processes

Inhibitory controlBehavioural regulation and control of attention

Working memoryAbility to keep information in mind and manipulate it

Cognitive flexibilityAbility to switch between tasks efficiently and consider information from a different perspective

Lezak et al.Neuropsychiatric Assessment 2004Vogels et al. Eur J Heart Failure 2007Calderon et al, Cardiol in Young 2015

Allows an individual to:• Develop and carry out plans• Solve problems• Function in social structures• Adapt to unexpected circumstances

If impaired:• Disorganised• Impulsive• Hyperactive +- Aggressive

How to assess executive function?

Lezak et al. 2004Bauer et al. 2006

• Real world scenarios best

• IQ can be normal in the setting of significant executive dysfunction– Clue: working memory subscale

• Impairments in:– set shifting ability

– task-oriented behaviour

Why do we anticipate higher rates of neurodevelopmental difficulties in ACHD patients?

Many were children with developmental problems

Marino et al, Circulation, 2012

“Among pediatric patients with complex CHD, there is a distinctive pattern of neurodevelopmental and behavioral impairment”

• Mild cognitive impairment • Impaired social interaction + core communication skillis

• Inattention and impulsive behaviour• Impaired executive function

These problems do not disappearwhen children become adolescents or adults.

Children can ‘grow into their deficits’Defects ‘emerge’ as demands of life increase

Social factors

Cardiac surgery

Disease related

Cognitive dysfunction

• Age at repair

• CPB, circ arrest

• Post-operative instability

• Absence from school

• Poor peer interaction

• Severity of condition

• Genetic syndromes

• Prolonged cyanosis

• Seizures

• Strokes

TERTIARY BRAIN DAMAGEBrain changes predispose a patient to further injury or prevent repair

ADDING INSULT TO INJURYAs life expectancy increases, so does opportunity for repeated brain injury

Marelli at el. Circulation 2016

Additional insults in adulthood?

Which of the following have been associated with

cognitive dysfunction in adults?

a. Heart failure

b. Atrial fibrillation

c. Critical illness

d. Stroke

e. All of the above

Heart failure

Cerebral hypoperfusion(reduced CO)

Cardiogenic embolism

Cognitive deficits

Bauer et al. Eur J Card Nurs 2012Bennett et al. J Cardiovasc Nurs 2003 Cacciatore et al. J Am Geraitr Soc 1998

Pressler et al. 2008 J CV Nurs 2008Trojano et al. J Neurol 2003Woo et al. J Cardiac Failure 2005Vogels et al. Eur J Heart Fail 2007Zuccala et al, Am J Med 2003Zuccalas et l. Neurology 2001

• Impairment in 1 or more cognitive domains (esp. memory and executive function) in 28-58% of patients with HF

Arrhythmias #3

AF associated with higher risk of cognitive impairment (regardless of stroke) with a RR ~ 1.5

50% patients with severe CHD develop atrial arrhythmias by age 65(Bouchardi et al Circulation 2009)

?impact of repeat surgeryNEJM 2001

53

36

24

DISCHARGE 6 WEEKS 6 MONTHS

%

% of Patients with cognitive impairment

Critical illnessNEJM 2013

• 821 patients with respiratory failure or shock

• 90% ventilated, 60% coma

• Similar results in all age groups

RBANS = repeatable battery for assessment of neuropsychological status

Vulnerable host?

Social factors

Cardiac surgery

Disease related

Heart failure

Redo surgery or interventions

Strokes

Arrhythmias

Critical illness

Are there neuropathological changes in ACHD patients?

•Cognitive processing speed, executive functioning, attention, visual-motor skills rely on white matter integrity

Brewster et al. J Int Neuropsych Society 2015

White matter disruption (fractional anisotropy) evident using novel techniques in two areas

Brain-behaviour relationships established• Uncinate fasciculus correlated with verbal

memory• R middle cerebellar peduncle correlated

with attention span

Neuroimage 2015

N=49 TGA + ASO patients (29 controls)

Graph analysis techniques to diffusion tensor imaging (DTI)

Disruption of organisation of large-scale networks within the brain

Spring-loaded visualisation – fewer connections (gray lines) between intermodular connections in TGA cohort

Neuroimage Clinical 2014

Cyanotic CHD (n=10)• Marked macro and microvascular injury• Extensive gray and white matter loss• Local cortical (frontal lobe) and subcortical

thickness reduction • Possibly mediated by inflammation and

endothelial dysfunction• GM volume loss ⍶ hsCRP, BNP, ADMA

Does this translate into cognitive deficits in adults with congenital heart disease?

Title

Text

Cardiology in the Young 2014

• Search of six databases • Inclusion criteria:

• Adults with CHD + objective cognitive assessment• English language, peer-reviewed publications

• 5 articles only identified• One was a subset analysis of another

Sample Control Cardiac defect

Assessment tool

Utens1

(Netherlands)

N=242Mean age 22Cross-sectional

Reference group

Mixed(ASD, TOF TGA)

Groniger intelligence test (Short form)

Wernovsky2

(Boston)

N=133Mean age 14

Normed population data

Fontan Age appropriate IQ test(WAIS)

Eide3

(Norway)

N=166Mean age 19Retrospectivecohort

384 000 healthy army recruits

Mixed(TGA, VSD/ASD)

Validated Norwegian IQ test

Daliento4

(Italy)

N=54Mean age 32

Reference group

TOF Raven’s matrices for IQAND 11 tests to evaluate other domains

1J Psychosom Res 19942 Circulation 20003 Pediatr Res 20064Heart 2005

IQ largely within normal range in these studies

• IQ lower in:• More complex disease• Cyanosis

Tyagi et al. Cardiol in the Young 2014Wernovsky et al. Circulation 2000

Murphy et al. Child Neuropsychology 2017

N=18 post TOF or TGA surgerySibling matchedIQ (WAIS), attention (self-report)

• Lower full scale IQ 96 v 103• Relative strength in verbal

comprehension

• Attention problems higher in CHD patients (self report and mother report)

Kalfa et al. JCTVS 2017

• N= 67 with TGA + ASO(43 matched controls)

• Mean age 23• IQ (WAIS): Mean IQ 95 v 103*

• Risk factor:• Older age at surgery

*P<0.001

Little research on specific areas of cognitive function

• IQ scores are gross measures of overall cognitive functioning

• May mask a variety of subtle impairments

Frontiers in Paediatrics 2016

UCLAN=80 (76 controls)Memory testing (WRAML2)

• Significant memory deficits in immediate and delayed tasks in a high proportion of patients • 50% v 4% in healthy controls

• Predictor = number of surgeries• Verbal memory worse than visual memory

• visual educational material preferable at transition etc.

Title Heart 2005

• 54 patients with TOF (Italy)

– Mean age 32y

– Mean age 8y at operation. All CPB + deep hypothermia

• Battery of 11 tests

– IQ largely within normal range

Title

TextHeart 2005

Clear deficits in executive functioning

More likely if history of ‘blue spells’

*32nd Bethesda Guidelines Klouda et al. Congenital Heart Disease 2017

–Cohort study (n=48)• Adults 18-49y

• Moderate or severe CHD*

• Cardiac surgery for CHD <5y age

–Neurocognitive tests• Computer based test assessing a variety of domains

• BRIEF self-report form to assess executive function

Moderate• AVSD, Coa, Ebstein, TOF, VSDSevere• Cyanotic, Fontan, TGA

NICHE study, Texas

NICHE Study: deficits worse with complex disease

Severe vs. moderate• Worse in all domains• 6 fold increase in

‘moderate neurocognitive impairment’

Moderate• AVSD, Coa, Ebstein, TOF, VSDSevere• Cyanotic, Fontan, TGA

NICHE study : Executive impairment in severe CHD

Executive functioning strongly correlated to number of cardiac operations

Problems with emotional regulation in particular

Moderate• AVSD, Coa, Ebstein, TOF, VSDSevere• Cyanotic, Fontan, TGA, pulmonary atresia

Tyagi et al. Cardiology in the Young 2017

• Cross-sectional study at Heart Hospital, London (N=310)

• Battery of 15 tests• IQ within normal range• 41% showed impaired

function on at least 3 tests • Significant executive

dysfunction• Stroop, WCST, TMTB

SINGLE VENTRICLE

TRANSPOSITION

TETRALOGY

SIMPLE

Implications of cognitive impairment in ACHD patients

•Adherence

• Ability to manage complex treatment regimens

• Ability to assess and self-manage symptoms

•Ability to understand patient education

• Loss to follow-up

•Medical consent

Implications of cognitive impairment in ACHD patients

•Association with social functioning1

• Specific impairments in theory of mind (esp. ‘third person’)2

• Eg. Pragmatic language impairment, difficulty reading social cues

• May limit ability to form healthy relationships

•Association with psychiatric disorders3

• 3 x general population

•Association with ADHD4 5

• Up to 1/3 1Marino et al, Circulation 20122Chiavarino et al. J Health Psych 20133Kovacs et al, Int J Card 20094Hansen et al. Pediatr Int 20125Yamada et al. Can J Card 2013

Identification: may be subtle

May manifest as:–Workplace or Education issues

–Poor grades or ‘Learning disability’ at school–Struggling with higher education–Difficulty holding a job

–Behavioural issues–Crime, addiction, risk-taking

–Psychological issues–Difficulties with social / intimate relationships

Royall et al. J Am Geriatr Soc 1992Schillerstrom et al. Psychosomatics 2005

What to do once suspect cognitive dysfunction?

•No good screening tests• Clinical history and collaborative history• MMSE not useful

• Formal assessment?• Neuropsychologist+- vocational/educational counselling+- community living assessment (OT)

•Assess for associated psychological issues

(How) can we intervene?

Interventions: Compliance, self-management

• No specific interventions documented in literature for ACHD patients

• Compensatory mechanisms• Modify communication re medical condition

• Repetition, multiple modalities (verbal, written)• Educational materials• “Internet-delivered health behaviour change interventions”

• Frequent medical contact• Role of nurse practitioner

Interventions for executive dysfunction

•Metacognitive approaches1 2

•Goal management training (GMT)• Rehabilitation technique (Acquired brain injury)• Complex tasks divided into smaller tasks

•Working memory training3 4

• Structured computer based programs (eg Cogmed)

1Levine et al. J Int Neuropsychol Soc 20002Krasny-Pacini et al. Disabil Rehabil 20143Soderqvist et al. Dev Psychol 20124Rueda et al. Dev Coogn Neurosci 2012

InterventionsPharmacological therapy?

• Methylphenidate• Improved executive function in ADHD patients1 2

• Arrhythmia / MI risk in ACHD patients?3 4

• Sertaline• Improved executive function in depressed patients

with mild TBI5

1Kuperman et al. Ann Clin Psych 20012Meyers et al. J Clin Oncol 19983Shin et al. BMJ 20164Sinha et al. Case Rep Cardiol 20165Fann et al. Psychosomatics 2001

InterventionsImprove oxidative or perfusion deficits?

•Oxygen• Improved executive function seen in patients with OSA or CHF

with O2 therapy1 2

• Exercise?• RCT in CHD (TOF, Fontan)

• Improved self-reported cognitive functioning and parent-reported social functioning 3 4

•Cardiac resynchronisation therapy in HF1Andreas et al. J Am Coll Card 199623Richards et al. J Neurol Neurosurg Psych 19973Hillman et al. Nat Rev Neurosci 20084Dulfer et al. J Adolesc Health 2014

Interventions

Cardiac resynchonisation therapy: A pilot study examining cognitive change in patients before and after treatment

0

10

20

30

40

50

60

70

Digit span TMT A Digitsymbol

TMT B COWA

Pre

Post

Dixit et al. Clin Cardiol 2010

P=0.02

P=0.83

P=0.001

P=0.17 P=0.01

Conclusions

•Vulnerable host to ongoing insults

• Intelligence (IQ) often within normal range

• Specific (and subtle) deficits may exist• Executive dysfunction common

•May affect other domains • Work, education, social functioning

•Heightened awareness important but no ideal screening test

• Interventions are predominantly compensatory

Who is at risk?

1. Neonates or infants requiring open heart surgery

2. Other cyanotic lesions not requiring early surgery

3. Any CHD and a co-morbidity below• Prematurity

• Genetic abnormality or syndrome

• CPR at any point, history of mechanical support (ECMO)

• Prolonged hospitalisation (post op LOS > 2 weeks)

• Perioperative seizures

Marino et al. Circulation 2012

Functional impact of executive dysfunction

• Self-management

• Compliance and resistance to care

• Level of care, ability to live alone

• Medical decision-making capacity, informed consent

• Mood disorder (eg Apathy)

Schillerstrom et al. Psychosomatics 2005

Cyanosis

• Often used as a proxy fordisease complexity• Utens:

• Lower Mean IQ if cyanotic condition

• Daliente : • TOF + blue spells– Attention/concentration

(Trail Making A & B)

– Executive function (planning)(Tower of London tasks)

NICHE results (48 patients)

Moderate CHD

• No significant difference vs. normative samples

Severe CHD

• Significant differences in – Neurocognitive index

– Processing speed

– Psychomotor speed

– Reaction time

– Complex attention

Future challenges for studies

• IQ testing vs. broader cognitive assessment

• Study total population • ? Combined population (vs. single diagnosis)

Generalisability of findings

Specific conditions may bias findings

Heterogeneity may dilute specific effects

Be

nef

its

Disad

vantages

Future directions

Define impact of

a condition

Related treatment

s

Longitudinal

follow-up

?modifiable factors

Eg medical or psychosocial

IQ test v broader Ax

Single diagnosis v combined population

Generational effect

Manifestations of executive dysfunction

May explain some of common occurrence of:

• disorganised,

• hyperactive,

• impulsive and

• sometimes aggressive behaviour

• Remove?

?modifiable factors Eg medical or

psychosocial

Define impact of a condition

Related treatments

Longitudinal follow-up

Atrial fibrillation

Mechanisms?

• Shared risk factors

• DM, HT, CHF

• Cardioembolism

• Cerebral hypoperfusion – low CO

• Beat to beat variability in cardiac cycle length

• Loss atrial contraction

• Periventricular white matter lesions

Bunch et al Heart Rhythm 2010Elias et al. J Stroke Cerevrovasc Dis 2006Kalantarian et al Ann Int Med 2013

Interventions

• Vocational or educational counselling

• Community living skills

Marino et al Circulation 2012Kamphuis et al. Arch pediatr adolesc med 2002